The applicant's professional career demonstrates a long-term committment to patient-oriented research, extensive experience in the study of the role of the vascular endothelium in the regulation of peripheral vasomotor tone in patients with heart failure, and a strong record in mentoring fellows for careers in patient-oriented research. The Division of Circulatory Physiology at Columbia has committed to protect 50 percent of the applicant's time for grant-supported research. The applicant's research efforts are further supported by the Department of Medicine and ongoing NIH and AHA grants. This Midcareer Investigator Award in Patient-Oriented Research will provide support to expand ongoing research efforts into new directions and create a comprehensive mentoring program for young clinical investigators. The overall aim of this research proposal is to characterize the pathophysiology of endothelial dysfunction in heart failure in order to devise new therapeutic strategies for the treatment of heart failure. Preliminary data demonstrate that endothelial function can be assessed non-invasively by measurement of flow-mediated vasodilation (venous occlusion plethysmography and Doppler ultrasongography) and by measurement of nitric oxide synthesis (stable isotope tracer techniques with 15N-L-arginine and measurement of nitric oxide in exhaled gases), that endothelial dysfunction in heart failure is partly attributable to a diffusable factor present in the serum, and that endothelial dysfunction may be linked to increased oxidative stress. We now propose 1) to characterize the prevalence, natural history, and prognostic implications of endothelial dysfunction in heart failure; 2) to characterize the effects of the diffusable serum factor present in patients with heart failure in cultured endothelial cells; and 3) to determine whether specific antioxidant therapies can reverse endothelial dysfunction in patients with heart failure. The mentoring program will consist of three key components: 1) intensive practical training in patient-oriented research (participation in the protocols described in this research plan and creation of an independent research project); 2) Columbia University didactic programs on clinical trial design, data analysis in clinical research, grant writing, and ethical issues in clinical research; 3) ongoing review of trainee progress by a committee of internationally-recognized patient-oriented research experts at Columbia.